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International Journal of Molecular Sciences

Review Association of Polymorphisms of MASP1/3, COLEC10, and COLEC11 with 3MC Syndrome

Gabriela Gajek * , Anna S. Swierzko´ and Maciej Cedzy ´nski Laboratory of Immunobiology of Infections, Institute of Medical Biology, Polish Academy of Sciences, 93-232 Lodz, Poland; [email protected] (A.S.S.);´ [email protected] (M.C.) * Correspondence: [email protected]

 Received: 30 June 2020; Accepted: 30 July 2020; Published: 31 July 2020 

Abstract: The Malpuech, Michels, Mingarelli, Carnevale (3MC) syndrome is a rare, autosomal recessive genetic- disorder associated with mutations in the MASP1/3, COLEC1,1 or COLEC10 genes. The number of 3MC patients with known mutations in these three genes reported so far remains very small. To date, 16 mutations in MASP-1/3, 12 mutations in COLEC11 and three in COLEC10 associated with 3MC syndrome have been identified. Their products play an essential role as factors involved in the activation of complement via the or alternative (MASP-3) pathways. Recent data indicate that mannose-binding lectin-associated serine -1 (MASP-1), MASP-3, collectin kidney-1 (collectin-11) (CL-K1), and collectin liver-1 (collectin-10) (CL-L1) also participate in the correct migration of neural crest cells (NCC) during embryogenesis. This is supported by relationships between MASP1/3, COLEC10, and COLEC11 mutations and the incidence of 3MC syndrome, associated with craniofacial abnormalities such as radioulnar synostosis high-arched eyebrows, cleft lip/palate, hearing loss, and ptosis.

Keywords: 3MC syndrome; MASP1/3; COLEC11; COLEC10; MASP-1; MASP-3; CL-K1; CL-L1

1. Introduction The Malpuech, Michels, Mingarelli and Carnevale syndrome [1–4] is commonly called 3MC syndrome. In 1989, Carnevale et al. reported a phenotype consisting of downslanting palpebral fissures, ptosis of the eyelids, periumbilical depression, hypertelorism, radioulnar synostosis, and developmental delay in two Italian siblings (MIM 265050). In 1996, two sisters with similar ocular, facial, skeletal, and abdominal defects, but with normal intelligence, were reported by Mingarelli et al. (also MIM 265050). Since the clinical picture of patients suffering from Carnevale and Mingarelli syndromes overlapped with Michels (MIM 257920) and Malpuech syndromes (MIM 248340), it was suggested that all four disorders should be reclassified into one “3MC syndrome”. It is a rare, autosomal recessive genetic disorder, characterized by a wide spectrum of developmental abnormalities that could include high-arched eyebrows, cleft lip/palate, hearing loss, short stature, umbilical hernias/omphalocele, and urogenital abnormalities. The prevalence of 3MC syndrome is unknown. The largest number of affected persons is located in the Middle East. 3MC syndrome disorders are caused by mutations in the mannose-binding lectin-associated (MASP)1/3 [5], COLEC11 [6], or COLEC10 [7] genes. The number of 3MC patients carrying known mutations in these three genes reported so far still remains rather small but the disease is more likely to occur in families with consanguineous parents. In total, forty-six 3MC patients from 34 families with mutations in the above-mentioned genes have been diagnosed. Among them, 26 persons from 20 families had mutations in the MASP1/3 (Table 1), 17 individuals from 12 families had mutations in the COLEC11 (Table 2), and three patients from two families had mutations in the COLEC10 gene (Table 3). Those mutations abort or impair function of their corresponding , resulting in defective control of cell migration at an early stage of

Int. J. Mol. Sci. 2020, 21, 5483; doi:10.3390/ijms21155483 www.mdpi.com/journal/ijms Int.Int. J. Mol.J. Mol. Sci. Sci.2020 2020, 21, ,21 5483, x FOR PEER REVIEW 2 of2 14of 14

migration interferes with ontogenesis of tissues and organs and leads to the various abnormalities embryonal development [6]. Impaired cell migration interferes with ontogenesis of tissues and organs manifested. The proteins expressed are also factors involved in the activation of complement via the and leads to the various abnormalities manifested. The proteins expressed are also factors involved , an important branch of the innate [6,8]. It was suggested that in the activation of complement via the lectin pathway, an important branch of the innate immune dysfunction of the lectin pathway can be compensated by other defense mechanisms, which seems system [6,8]. It was suggested that dysfunction of the lectin pathway can be compensated by other to explain why immune system dysfunctions are not part of the 3MC syndrome. defense mechanisms, which seems to explain why immune system dysfunctions are not part of the 3MC2. The syndrome. MASP1/3 Gene and Its Products—MASP-1, MASP-3, and 2. The MASP1/3 Gene and Its Products—MASP-1, MASP-3, and MAp44 2.1. Gene and Structure 2.1. GeneThe and MASP1/3 Protein Structure gene is located on 3 (3q27-28). It contains 76 kbp and encompasses 18 Theexons. MASP1 This/3 gene gene isencodes located for on chromosometwo , 3 (3q27-28).MASP-1 Itand contains MASP-3 76 kbp(mannose-binding and encompasses lectin- 18 exons.associated This gene serine encodes ) for two as well enzymes, as the MASP-1non-enzymatic and MASP-3 MAp44 (mannose-binding (mannose-binding lectin-associated lectin-associated serineprotein, proteases) 44 kDa) as [9]. well All as three the non-enzymatic MASP1/3 alternative MAp44 splicing (mannose-binding products share lectin-associated four N-terminal protein, domains, 44 kDa)encoded [9]. All by three exons MASP1 2–8: /CUB1-EGF-CUB2-CCP13 alternative splicing products (explained share below), four N-terminal while exon domains, 1 encodes encoded the 5′- untranslated region [8]. Exons 10 and 11 encode the CCP2 domain, common to MASP-1 and MASP- by exons 2–8: CUB1-EGF-CUB2-CCP1 (explained below), while exon 1 encodes the 50-untranslated region3. Single [8]. exon Exons 12 10 is andresponsible 11 encode for the serine CCP2 domain,protease (SP) common domain to MASP-1of MASP-3, and whereas MASP-3. exons Single 13— exon18 are 12 isresponsible responsible for for the the corresponding serine protease MASP-1 (SP) domainfragment. of The MASP-3, ninth whereasexon encodes exons the 13—18 unique are C- responsibleterminal 17 for AA the sequence corresponding of MAp44. MASP-1 According fragment. to the The NCBI ninth database exon encodes a fourth the splice unique variant C-terminal has been 17recorded, AA sequence however of MAp44. the resulting According RNA to the does NCBI not database constitute a fourth mRNA, splice and variant presumably has been is recorded, degraded howeverthrough the the resulting nonsense-mediated RNA does notmRNA constitute decay pathway mRNA, and[10].presumably is degraded through the nonsense-mediatedTherefore, MASP-1 mRNA and decay MASP-3 pathway are [10proteases]. composed of six well-characterized domains, of whichTherefore, five constitute MASP-1 the and heavy MASP-3 chain are while proteases the sixth composed (SP) constitutes of six well-characterized the light chain. Upon domains, activation of whichof proenzymes, five constitute the the peptide heavy bond chain between while the them sixth is (SP) cleaved constitutes and both the chains light chain. remain Upon connected activation via a ofdisulphide proenzymes, bond the peptide[11,12]. The bond CUB between (C1r/C1s-Uegf them is cleaved (uchrin and epidermal both chains growth remain factor)-BMP connected (bone via a disulphidemorphogenic bond protein)) [11,12 ].and The EGF CUB (epidermal (C1r/C1s-Uegf growth (uchrin factor) epidermal domains growthare responsible factor)-BMP for forming (bone morphogenicMASP/MAp44 protein)) complexes and with EGF such (epidermal pattern-recognition growth factor) molecules domains (P areRM) responsible as collectins for and forming MASP[13]./ MAp44It should complexes be stressed with that such most pattern-recognition of the proteins molecules possessing (PRM) the asCUB collectins domain and are ficolins involved [13]. in It shoulddevelopmental be stressed processes, that most such of the as proteins bone morphogene possessingtic the protein CUB domain 1, the dorso- are involvedventral in patterning developmental protein processes,tolloid, sucha family as bone of spermadhesins, morphogenetic proteinand the 1, theneuronal dorso-ventral recognition patterning molecule protein A5 tolloid,[8,14]. aThe family CCP of(complement spermadhesins, control and theprotein) neuronal domains recognition are common molecule to A5a variety [8,14]. Theof complement CCP (complement factors control[15]. The protein)serine domainsprotease are(SP) common domain to with a variety catalytic of complement activity is characteristic factors [15]. The forserine -like protease (SP) domainproteases with[8].catalytic There are activity several is single characteristic nucleotide for polymorphi chymotrypsin-likesms of the proteases MASP1/3 [ 8gene]. There strongly are several associated single with nucleotideprotein serum polymorphisms levels. Among of the them, MASP1 homozygosity/3 gene strongly in associatedintron 8 (rs3774275, with protein G/G) serum was levels. associated Among with them,decreased homozygosity MASP-3 in but intron increased 8 (rs3774275, MASP-1 G/ G)and was MAp4 associated4. Variant with alleles decreased for rs698090 MASP-3 and but increasedrs67143992 MASP-1are associated and MAp44. with Variantan increase alleles in forMASP-1 rs698090 and and MAp44 rs67143992 and a aredecrease associated in MASP-3, with an while increase variant in MASP-1alleles andof rs72549154 MAp44 and and a decreasers35089177 in result MASP-3, in decre whileases variant of MASP-1 alleles ofand rs72549154 MAp44 and and an rs35089177 increase of resultMASP-3 in decreases [9], Figure of MASP-11. and MAp44 and an increase of MASP-3 [9], Figure1.

Figure 1. Scheme of mannose-binding lectin-associated serine protease-1 (MASP-1), MASP-3, and mannose-bindingFigure 1. Scheme lectin-associated of mannose-binding protein, 44lectin-associated kDa (MAp44) proteinserine structuresprotease-1 (acc.(MASP-1), to Gaboriaud MASP-3, et al., and 2013mannose-binding [16]. lectin-associated protein, 44 kDa (MAp44) protein structures (acc. to Gaboriaud et al., 2013 [16].

Int. J. Mol. Sci. 2020, 21, 5483 3 of 14

2.2. Tissue Expression of the MASP-1, MASP-3, and MAp44 MASP-1 is mainly expressed in the liver although specific mRNA was also found in the brain and cervix. Similarly, the major site of MASP-3 synthesis is the liver but its expression was also noted in a variety of other sites, including the colon, bladder, and uterus. MAp44 is synthesized in the heart while weaker expression takes place in the liver, brain, and cervix [10,17,18]. The expression of MASP-3 has been considered ubiquitous compared with other isoforms [10]. These results emphasize the importance of alternative splicing mechanisms in the regulation of expression in different tissues. The widespread expression of the MASP1/3 gene may indicate local functions of its products MASP-1, MASP-3, and MAp44. The median serum levels of MASP-1, MASP-3, and MAp44 in healthy adults were found to equal 10.8, 6.7 and 2.2 µg/mL, respectively. Concentrations of MASP-1 and MASP-3 showed gender differences—the first mentioned was higher in women while the second was higher in men [19]. Moreover, MASP-3 and MAp44 also correlate with age [19].

2.3. Biological Activities of the MASP-1, MASP-3, and MAp44 Mannose-binding lectin-associated serine protease-1 (MASP-1) functions as a factor involved in the activation of complement, , and –kinin systems. As mentioned, it exists in the form of a zymogen occurring in complexes with some collectins (MBL, collectin liver-1 (also known as collectin 10, CL-10), collectin kidney-1 (or collectin 11, CL-11)), and ficolins (ficolin-1, -2, -3 or M-, L-, H-ficolin, respectively). MASP-1 is auto-activated when the complex binds to the target, recognized by PRM (collectins and ficolins, as recognize mainly polysaccharides or glycoconjugates expressed on the surface of pathogens or abnormal self-cells). MASP-1 then cleaves MASP-2 zymogen (another protease of the MASP-2 family, encoded by the distinct MASP-2 gene), which next activates complement C4 factor. Both MASP-1 and MASP-2 further activate C2 forming C3 convertase (C4bC2a) (identical to that of the classical pathway) [20]. Moreover, MASP-1 is able to cleave fibrinogen, factor XIII, prothrombin, and -activatable fibrinolysis inhibitor (TAFI) thus promoting coagulation [21–24]. The clots can gather around microbes and hinder their spreading [25]. Furthermore, the high-molecular-weight kininogen was reported to be another MASP-1 substrate. Its digestion enables release of bradykinin, a pro-inflammatory mediator of the contact system [26]. Moreover, MASP-1 can activate endothelial cells [27], enhance endothelial E- expression [28], and increase the production of interleukins IL-6 and IL-8 [29]. MASP-3 is believed to contribute to the activation of complement via the alternative pathway through pro- cleavage [20]. Another substrate is insulin-like growth factor-binding protein 5 (IGFBP-5) that modulates the effects of IGF on cell survival, differentiation, and proliferation [30]. MAp44 functions as an inhibitor of the complement pathway by competing with MASP for PRM-binding sites [31]. It moreover contributes to regulation of cardiac development [32]. Some clinical associations of MASP-1, MASP-3, and MAp44 other than 3MC have been reported. For example, Weinschutz Mendes et al. (2020) found that polymorphisms influencing serum concentrations of MASP-3/MAp44 modulate susceptibility to leprosy [33]. Larsen et al. (2019) showed that low MASP-1 concentrations were associated with clotting disorders in patients with septic shock [34]. Michalski et al. (2019) demonstrated that children undergoing surgical correction of congenital heart disease with low pre-operative MAp44 concentration were more likely to suffer from post-operative complications such as systemic inflammatory response syndrome (SIRS), renal failure, multiorgan dysfunction (MODS), or low cardiac output syndrome (LCOS), while high MASP-1 and low MASP-3 were often associated with fatal outcome [35].

3. COLEC10 and COLEC11 Genes and Their Products, CL-L1 and CL-K1

3.1. Genes and Protein Structures Collectins constitute a group of 400–800 kDa oligomeric, calcium-dependent lectins consisting of basic subunits that are triplets of 30–35 kDa polypeptide chains. Collectin liver-1 (collectin-10) (CL-L1) Int. J. Mol. Sci. 2020, 21, 5483 4 of 14 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 4 of 14 and[36]. collectin The collectin kidney-1 polypeptide (collectin-11) chain (CL-K1) consists are of closelyan N-terminal related, bothregion structurally containing and cysteine, functionally a collagen- [36]. Thelike collectindomain polypeptidewith Gly-Xaa-Yaa chain consistsrepeats (where of an N-terminal Xaa and Yaa region represent containing any cysteine,amino acid a collagen-like residues), a domainneck region, with Gly-Xaa-Yaaand a C-terminal repeats carbohydrate-recognition (where Xaa and Yaa represent domain any (CRD). amino acidThe residues),CRD is responsible a neck region, for andinteractions a C-terminal with carbohydrate-recognitionsugar residues on microbial domain surfaces (CRD). or aberrant The CRD host is responsiblecells, whereas for the interactions collagen- withlike domain sugar residues forms complexes on microbial with surfaces proteins or aberrantof the MASP host cells,family whereas as well the as collagen-like interacting with domain cell formsreceptors. complexes CL-L1 and with CL-K1 proteins form of theheterocomplexes MASP family called as well CL-LK, as interacting existing within blood. cell receptors. Each molecule CL-L1 is andstabilized CL-K1 by form a disulphide heterocomplexes bridge (created called CL-LK, by Cys existingresidues in present blood. in Each N-terminal molecule domains) is stabilized with by two a disulphideCL-K1 and bridgeone CL-L1 (created polypeptide by Cys residues chains [37]. present CL-K1 in N-terminalis present in domains) species ranging with two from CL-K1 the zebrafish and one CL-L1to humans polypeptide (with protein chains identities [37]. CL-K1 of isfull present length in protein: species ranging72–98%). from The the protein zebrafish identity to humans between (with the proteinCRDs of identities CL-K1 and of full CL-L1 length reaches protein: 54%. 72–98%). This compares The protein with identity only 25–32% between for the the CRDs corresponding of CL-K1 anddomains CL-L1 of reachesother collectins. 54%. This [38]. compares with only 25–32% for the corresponding domains of other collectins.The human [38]. COLEC10 gene is localized to chromosome 8 (8q23–q24.1) and includes six exons. The Thefirst humanone encodesCOLEC10 for thegene untranslated is localized region, to chromosome the N-terminal 8 (8q23–q24.1) domain, and and the includes first Gly-Xaa-Yaa six exons. Thesequence first one of the encodes collagen-like for the untranslated region. The region,rest of the the collagen-like N-terminal domain, domain andis encoded the first by Gly-Xaa-Yaa exons 2–5. sequenceExon 5 is of also the responsible collagen-like for region. the sequence The rest of of al thepha-helical collagen-like coiled-coil domain neck is encoded region bywhile exons exon 2–5. 6 Exonencodes 5 is for also the responsible CRD domain for the [39]. sequence Twenty of polymorphi alpha-helicalc sites coiled-coil were identified neck region in whilethe promoter, exon 6 encodes exons, forand the flanking CRD domainregions [of39 ].the Twenty COLEC10 polymorphic gene [40]. sitesNone were of promoter identified polymorphisms in the promoter, were exons, found and to flankinginfluence regions CL-L1of serum the COLEC10 level. Thegene +3654 [40 C>T]. None polymo of promoterrphism polymorphisms(rs149331285, exon were 5) foundaffects to the influence protein CL-L1structure serum due level. to an The amino+3654 acid C> exchangeT polymorphism (p.Arg125Trp). (rs149331285, Heterozygosity exon 5) aff ectswas thedemonstrated protein structure to be dueassociated to an amino with acidsignificantly-higher exchange (p.Arg125Trp). CL-L1 serum Heterozygosity concentration, was compared demonstrated with to C/C be associatedhomozygosity. with significantly-higherMoreover, the -161/-157AAAATdel CL-L1 serum concentration, (rs148350292) compared may disturb with the C/ Cbinding homozygosity. of several Moreover, transcription the -161factors/-157AAAATdel essential for (rs148350292)liver development may disturbor immune the binding response of modulation several transcription [40]. factors essential for liver developmentThe COLEC11 or gene immune is localized response to modulationchromosome [40 2]. (2p25.3). It includes eleven exons, of which sevenThe encodeCOLEC11 for thegene dominant is localized isoform to chromosomeCL-11-1. With 2 the (2p25.3). exception It includes of the first eleven one exons,that encodes of which the sevenuntranslated encode region, for the dominantthe other six isoform exons CL-11-1. are arranged With theand exception encode similar of the firstregions one to that that encodes of the theCOLEC10 untranslated gene [39]. region, Several the other variations six exons in the are promoter, arranged andexons encode and introns similar regionshave been to thatidentified. of the COLEC10Among them,gene promoter [39]. Several polymorphism variations in the-9570 promoter, C>T (rs3820897) exons and was introns shown have to beeninfluence identified. CL-K1 Among serum them,level. The promoter non-synonymous polymorphism SNP -9570 (p.His219Arg) C>T (rs3820897) in exon was 7 (+39618 shown C>G, to influence rs7567833) CL-K1 has no serum impact level. on Theprotein non-synonymous concentration SNPin serum, (p.His219Arg) however init exonis suspected 7 (+39618 to Cinfluence>G, rs7567833) ligand hasbinding no impact [40], Figure on protein 2. concentration in serum, however it is suspected to influence ligand binding [40], Figure2.

Figure 2. Subunit and oligomeric structure of CL-LK. A total of three polypeptide chains of (two of CL-K1Figure and2. Subunit one of and CL-L1) oligomeric join to formstructure a heteromeric of CL-LK. subunit,A total of which three maypolypeptide further oligomerizechains of (two into of structuresCL-K1 and ranging one of fromCL-L1) dimer join to to hexamer form a (acc.heterome to Hansenric subunit, et al., which 2018 [41 may]). further oligomerize into 3.2. Tissuestructures Expression ranging of from theCollectin-Liver dimer to hexamer 1 and (acc. Collectin-Kidney to Hansen et al., 1 2018 [41]).

3.2. TissueThe tissue Expression expression of the Colle of bothctin-Liver CL-K1 1 and Collectin-Kidney CL-L1 is ubiquitous. 1 The highest expression of the first mentioned was found in the liver, kidney, adrenal gland, ovary and gallbladder (and to a lower The tissue expression of both CL-K1 and CL-L1 is ubiquitous. The highest expression of the first extent, in the lung, ovary, testis, and retina) whereas expression of CL-L1 was found mainly in the liver mentioned was found in the liver, kidney, adrenal gland, ovary and gallbladder (and to a lower extent, in the lung, ovary, testis, and retina) whereas expression of CL-L1 was found mainly in the liver and adrenal gland [38,41,42]. In the adrenal gland, CL-K1 was reported to be expressed in cells

Int. J. Mol. Sci. 2020, 21, 5483 5 of 14 and adrenal gland [38,41,42]. In the adrenal gland, CL-K1 was reported to be expressed in cells of all three layers—spinal, banded, and reticular, whereas in the kidney, it is expressed in the distal canals, as well as the glomeruli and proximal tubules [38]. In the ovary, it is associated with granulosa and theca lutein cells while in the testis, the main expression sites are seminiferous tubules [38]. In the liver, the expression of both CL-K1 and CL-L1 is associated with hepatocytes [38,43]. Furthermore, high expression of both collectins was detected in placenta [42]. Average human CL-L1 serum level was estimated to be 0.5 µg/mL, while CL-K1 was estimated to be approximately 0.4 µg/mL. Their concentrations are strongly correlated [19]. No significant differences with sex, age (18–70 years), or diurnal variations were found [19,40,44,45].

3.3. Biological Activity of Collectin-Liver 1 and Collectin-Kidney 1 CL-K1 was reported to recognize certain Gram-negative bacteria (E. coli O126 and O60, Pseudomonas aeruginosa, and Klebsiella pneumoniae), mycobacteria (Mycobacterium tuberculosis), fungi (Candida albicans and Saccharomyces cerevisiae), and viruses (influenza A virus) [38,42,46]. Surface structures identified amongst those recognized by CL-K1 include (LPS core region of E. coli mutants of Ra and Rd, but not Re chemotypes), S. cerevisiae mannan, mycobacterial mannosylated lipoarabinomannan (ManLAM) [42,46], and HIV gp120 [47]. Venkatraman Girija et al., (2015) demonstrated the affinity of CL-K1 to mannose-rich glycans containing the disaccharide Man(α1-2)Man as terminal motif [47]. The microbial structures recognized by CL-L1 are not yet established, but formation of heterodimers with CL-K1 could possibly lead to an increased range of interactions with microorganisms, as well as to their higher affinity. Thus, CL-LK is characterized by high affinity to d-mannose (d-Man), n-acetyl-d-glucosamine (d-GlcNAc), d-galactose (d-Gal), l- and d-fucose (l-Fuc, d-Fuc), and n-acetyl-d-mannosamine (d-ManNAc) [41]. CL-LK, due to cooperation with MASP, may initiate activation of complement via the lectin pathway (and cross-talk with the coagulation cascade). They may also aggregate and opsonize microorganisms contributing to enhanced [48]. Through the collagen-like domain, but also via its CRD, CL-K1 binds to mammalian and bacterial DNA in a calcium-independent manner [49]. It also binds to DNA exposed on apoptotic/necrotic cells and may facilitate their clearance, preventing formation of anti-DNA antibodies. The CL-K1–DNA interaction may lead to complement activation. However, it is much weaker compared to other collectins, probably due to different degrees of protein oligomerization [50]. Only a few reports concerning CL-LK disease associations and the clinical significance of CL-L1/CL-K1 have been published to date. Increased blood CL-L1 levels were observed at early stages of acute liver failure and cirrhosis. Smedbråten et al. (2017) reported that high plasma concentrations of CL-L1 and CL-K1 at the time of transplantation are correlated with increased mortality in kidney transplant recipients [51]. Troldborg et al. (2018) found lower CL-L1 and CL-K1 levels in systemic lupus erythematosus (SLE patients), compared with healthy controls, however no association with SLE disease activity index (SLEDAI) score was found [52]. Storm et al. (2014) reported that CL-L1 may significantly distinguish between patients with colorectal cancer (CRC), patients with adenomas, and individuals without neoplastic bowel lesions [53]. Higher levels of CL-L1 were associated with lower odds of CRC [53]. Swierzko´ et al. (2018), reported higher serum levels of CL-LK complex in multiple myeloma patients compared with healthy individuals [45]. Farrar et al., (2016) showed that deficiency of CL-K1 is protective in the case of ischemia, preventing tubular damage and loss of renal function [54]. Similar conclusions were also drawn by Wu et al. (2018), who demonstrated that CL-K1 plays a harmful role in the development of tubulointerstitial fibrosis by leukocyte chemotaxis and the impact on the proliferation of renal fibroblasts [55]. Koipallil Gopalakrishnan Nair et al. (2015) observed an approximately 3-fold increase in CL-K1 and CL-L1 transcript expression in human ectopic endometriotic mesenchymal stem cells (MSCs) in comparison with eutopic MSCs [56]. Int. J. Mol. Sci. 2020, 21, 5483 6 of 14

4. Associations of COLEC10, COLEC1,1 and MASP1/3 Gene Mutations with 3MC Syndrome Association of MASP1/3 gene polymorphisms with 3MC were first reported by Sirmaci et al. (2010), in three individuals from two related Turkish families. They found a missense c.2059 G>A (p.Gly687Arg) mutation specific to the MASP-3 isoform and nonsense c.870 G>A (p.Trp290*) in exon 6, which is shared by all gene products. In silico results suggested that the p.Gly687Arg mutation may be damaging for the MASP-3 catalytic domain [5]. Other abnormalities of the same gene were identified by Rooryck et al. (2011). They described three homozygous missense mutations, all located within exon 12, encoding the MASP-3 protease domain, in the 3MC-syndrome-affected patients (c.1489C>T p.His497Tyr, c.1888T>C p.Cys630Arg, and c.1997G>A p.Gly666Glu). All of them are predicted to affect protein activity [6]. Atik et al. (2015) reported two splice site mutations, c.1012 - 2 A>G in one proband and c.891 + 1 G >T in two propositi, as well as three missense mutations, c.1451 G>A (p. Gly484Glu), c.1657 G >A (p. Asp553Asn), and c.1987 G >T (p. Asp663Tyr) in three other propositi. Splice site mutations affect both MASP-1 and MASP-3, while missense mutations affect MASP-3 only. A total lack of lectin pathway activity and a 2.5-fold lower alternative pathway activity in a proband homozygous for c.891 + 1 G > T were found [57]. Urquhart et al. (2016) identified three other mutations within the MASP1/3 gene (c.9 G>A p.Trp3*, c.547 G>T p.Val183Leu, and c.760 A>T p.Leu254*) [58]. The missense alteration, p.Asp663Tyr (reported also, as mentioned, by Atik et al. (2015)) probably changes the enzymatic activity of the catalytic domain [58]. Pihl et al. (2017) described the proposita from a German family with a homozygous missense mutation c.1993G.A (p.G665S) in exon 12 of the MASP1/3 gene, confirming the clinical diagnosis of 3MC syndrome. The serum concentration of MASP-3 in this patient was lower than the median for a healthy population [59]. Later, Graul-Neumann et al. (2018) reported a Turkish individual carrying a deletion of 2306 bp (c.1895_*1602+411del). It affects the terminal part of exon 12 and accordingly the C-terminal serine protease domain specific to MASP-3 [60]. A separate study of two individuals from a Turkish family was conducted by Basdemirci et al. (2019). They identified a new missense homozygous mutation c.2111T>G (p. Val704Gly) (NM_139125.3) in exon 11 of the relevant gene [61]. Çakmaklı et al. (2019) found the afore-mentioned missense c.1987G>T; (p.Asp663Tyr) MASP1/3 mutation (in a homozygous state) in a patient from Syria [62]. In summary, so far 16 3MC-syndrome-associated mutations in the MASP-1/3 gene in 26 individuals have been reported (Table1). The majority of them (11) a ffect the serine protease domain of MASP-3. Rooryck et al. (2011) demonstrated an association of homozygosity for three non-synonymous mutations and one in-frame deletion in the COLEC11 gene: c.496 T>C (rs387907075, p.Ser169Pro, exon 8), c.45delC (RCV000023960, p.Phe16Serfs X85, exon 2), c.610 G>A (rs387907076, p.Gly204Ser, exon 8), and c.648-650delCTC (RCV000023962, p.Ser217del, exon 8). Moreover, they identified a 27-kb homozygous deletion encompassing exons 1–3 of COLEC11, predicting partial loss of the collagen-like domain, and complete loss of the N-terminal (cysteine-rich) domain. Furthermore, a homozygous single-base deletion (c.300delT/G101VfsX113 in exon 6) was suggested to lead to premature termination of the COLEC11 gene product [6]. Gardner et al. (2017) identified a homozygous C-terminal deletion resulting in the complete loss of exon 8 and the partial loss of the carbohydrate-recognition domain [63] while Urquhart et al. (2016) reported a frame-shift mutation (deletion of two nucleotides), c.627_628delGC and p. (Ala213Leufs 5) [58]. Carriers of the above-mentioned mutations are suspected to be CL-K1-functionally-deficient. Two novel non-synonymous homozygous COLEC11 mutations in 3MC patients were later described by Munye et al. (2017). One of them, c.309delT (p.Gly104Valfs29 in exon 4) again seems to predict premature appearance of a stop codon, while another one, c.G496A (p.Ala166Thr in exon 6), causes a change in the structure, affecting protein activity. Additionally, they found deletion of 10 nucleotides (89_98del ATGACGCCTG in exon 2) which predicted a frameshift change and the introduction of a premature stop codon (p.Asp30Alafs68) [7]. To summarize, 11 mutations have so far been described in the COLEC11 gene in 17 3MC patients (Table2). Six of them a ffect the CRD region of the collectin. Int. J. Mol. Sci. 2020, 21, 5483 7 of 14

Table 1. Families affected by the Malpuech, Michels, Mingarelli, Carnevale (3MC) syndrome, associated with mutations in MASP1/3 gene.

Family (Number of Amino acid Change/Protein Origin Nucleotide Change References Carriers) Change c.2059G>A p.Gly687Arg F1 (2) Turkey exon 12 MASP-3 SP Sirmaci et al., 2010 [5] p.Trp290* c.870G>A F2 (1) Turkey MASP-1/3 exon 6 CUB1-EGF-CUB2-CCP1 c.1489 C>T p.His497Tyr F3 (1) Greece exon 12 MASP-3 SP c.1888T>C p.Cys630Arg F4 (2) Italy exon 12 MASP-3 SP Rooryck et al., 2011 [6] c.1997G>A p.Gly666Glu F5 (1) Brazil exon 12 MASP-3 SP c.1997G>A p.Gly666Glu F6 (1) Brazil exon 12 MASP-3 SP c.1012-2A>G F7 (1) Turkey Splice site mutation intron 7 c.891 +1G>T F8 (1) Turkey Splice site mutation intron 6 c.891 +1G>T F9 (1) Turkey Splice site mutation intron 6 Atik et al., 2015 [57] c.1451G>A p. Gly484Glu F10 (1) Pakistan exon 12 MASP-3 SP c.1657G>A p. Asp553Asn F11 (1) Turkey exon 12 MASP-3 SP c.1987G>T p. Asp663Tyr F12 (1) Syria exon 12 MASP-3 SP c.1987G>T p.Asp663Tyr F13 (1) Israel exon 12 MASP-3 SP p.Trp3* c.9G>A F14 (1) Sri Lanka MASP-1/3 exon 2 CUB1-EGF-CUB2-CCP1 Urquhart et al., 2016 [58] p.Leu 254* c.760A>T F14 (2) Sri Lanka MASP-1/3 exon 6 CUB1-EGF-CUB2-CCP1 p.Val 183Leu c.547G>T F15 (1) India MASP-1/3 exon 4 CUB1-EGF-CUB2-CCP1 c.1993G>A p.G665S F16 (1) Germany Pihl et al., 2017 [59] exon 12 MASP-3 SP p. Trp3* c.9G>A F17 (1) Pakistan MASP-1/3 Munye et al., 2017 [7] exon 2 CUB1-EGF-CUB2-CCP1 c.1895_*1602+411del p.Arg637Cysfs*1 Graul-Neumann et al., 2018 F18 (1) Turkey exon 12 MASP-3 SP [60] c.2111T>G p. Val704Gly F19 (3) Turkey Basdemirci et al., 2019 [61] exon 12 MASP-1/MASP-3 CCP2 c.1987G>T p.Asp663Tyr F20 (1) Syria Çakmaklı et al., 2019 [62] exon 12 MASP-3 SP

Three mutations of the COLEC10 gene were found associated with 3MC syndrome: c.25 C>T (exon 1), c.226delA (exon 3), and c.528 C>G (exon 6). The last-mentioned results in severe impairment of protein secretion, whereas the two others lead to the nonsense-mediated decay of transcripts [7]. All mutations in the COLEC10 gene occurring in patients with 3MC syndrome are shown in Table3. Int. J. Mol. Sci. 2020, 21, 5483 8 of 14

Table 2. Families affected by 3MC syndrome, associated with mutations in the COLEC11 gene.

Family (Number of Amino Acid Change/Protein Origin Nucleotide Change References Carriers) Change c.496T>C p.Ser169Pro F1 (2) Tunisia exon 8 CRD c.45delC p.Phe16SerfsX 85 F2 (2) Bangaldesh exon 2 N-terminal Collagen-like region c.610G>A p.Gly204Ser F3 (2) Afganistan exon 8 CRD c.648_650delCTC p.Ser217del F4 (1) Saudi Arabia exon 8 CRD Rooryck et al., 2011 [6] c.610G>A p.Gly204Ser F5 (1) Pakistan exon 8 CRD c.300delT p.Gly101ValfsX 113 F6 (1) Italy exon 6 Neck domain Predicted: complete loss of ex 1-3 deletion N-terminus and partial loss of the F7 (1) Italy exons 1,2,3 collagen-like domains N-terminal collagen-like region c.627_628delGC p. Ala213Leufs 5 F8 (2) Israel Urquhart et al., 2016 [58] Exon 8 CRD Predicted: complete loss of C ex 8 deletion terminus and at least partial loss of F9 (2) Pakistan Gardner et al., 2017 [63] exon 8 the carbohydrate-recognition domain (CRD) c.309delT p.Gly104Valfs29 F10 (1) Pakistan exon 4 Collagen-like domain c.G496A p.Ala166Thr F11 (1) Somalia exon 6 Neck domain Munye et al., 2017 [7] 89_98del United Arab p.Asp30Alafs68 F12 (1) ATGACGCCTG Emirates N-terminal domain exon 2

Table 3. Families affected by 3MC syndrome, associated with mutations in COLEC10 gene.

Amino Acid Family (Number of Nucleotide Origin Change/Protein References Ccarriers) Change Change c.25C>T p. Arg9Ter exon 1 Signal peptide F1 (2) Pakistan c.226delA p.Gly77Glufs*66 exon 3 Collagen-like region Munye et al., c.25C>T p. Arg9Ter 2017 [7] exon 1 Signal peptide F2 (1) Pakistan c.528C>G p.Cys176Trp exon 6 Neck domain

5. Concluding Remarks The craniofacial disruptions observed in patients suffering from 3MC syndrome are similar to neural crest migration disorders. The proper migration of neural crest cells (NCC) is essential for the formation of bones, cartilage, ganglia, and muscles in the head [64]. Control and regulation of NCC migration is complex and involves many genetic pathways. Thus, there is a possibility that proteins with collagen-like regions linked to a CRD domain play dual roles, contributing to immunity and development. Certain complement components have previously been shown to play an essential role in cell migration. and its C3aR receptor co-attracted crest cells, to coordinate migration in the first stages of NCC regulation [65]. Furthermore, surfactant protein D [66,67] and [68] being collectins (although lacking complement activation property), have been also described as chemoattractants. Studies employing zebrafish [6] demonstrated that loss of CL-K1 and MASP-1/-3 is Int. J. Mol. Sci. 2020, 21, 5483 9 of 14 associated with craniofacial abnormalities. Both proteins were proposed to act as guidance cues for neural crest cell migration [47]. Moreover, CL-L1 was shown to regulate development of craniofacial structures acting as a migratory chemoattractant [7]. Three CL-K1 gene mutations associated with 3MC syndrome, resulting in Ser169Pro and Gly204Ser substitutions and Ser217 deletion, prevent normal secretion from mammalian cells due to structural changes caused by the failure to bind Ca2+ during biosynthesis. The destabilization of CRD probably leads to elimination of protein via the endoplasmic-reticulum-associated protein degradation pathway [47]. Gorelik et al. (2017) also reported that MASP-1 plays an important role in radial neuronal migration in the development of the cerebral cortex. Deficiency of MASP-1 and other components of the lectin pathway (C3 and MASP-2) leads to impairments in radial migration resulting in improper positioning of neurons and disorganized cortical layers [69]. Because CL-LK heterocomplexes were found to bind MASP-1 or MASP-3 homodimers via their collagen-like regions [47,70] it is possible that correct migration of neural crest cells requires cooperation between CL-LK and MASP-1/-3. This may be supported by the relationship between MASP1/3, COLEC10, and COLEC11 mutations and the incidence of 3MC syndrome, associated with craniofacial abnormalities. During embryogenesis, these three genes are strongly expressed in the craniofacial cartilage, palatal structures, bronchi, heart, and kidneys and the corresponding proteins act as chemoattractants for the cranial crest nerve cells (crucial for the formation of the head skeleton), recognizing certain endogenous carbohydrate epitopes [6]. It should be however mentioned, that mice with knockout in MASP1/3 or COLEC11 genes developed normally and no defects similar to 3MC syndrome were noticed [71–73]. It moreover still remains to be clarified which defense pathways may compensate for MASP-1/3, CL-L1, and CL-K1 dysfunctions and why this rare disease is generally not accompanied by impaired immune response. As mentioned, so far 11 mutations in the COLEC11 gene, three in the COLEC10 gene, and 16 in the MASP1/3 gene associated with 3MC syndrome have been described. Further studies, however, are necessary to better understand the mechanisms by which dysfunction of MASP1/3, COLEC10, and COLEC11 genes may lead to the 3MC syndrome.

Author Contributions: Conceptualization, G.G. and A.S.S.;´ writing—original draft preparation, G.G.; writing—review and editing: G.G., A.S.S.´ and M.C.; supervision, M.C. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding Acknowledgments: The authors are very grateful to David C. Kilpatrick for critical reading of the manuscript and helpful discussion. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations

3MC Malpuech, Michels, Mingarelli, Carnevale syndrome MASP Mannose-binding lectin-associated serine proteases MAp44 Mannose-binding lectin-associated protein, 44kDa SP Serine protease BMP Bone morphogenic protein SNP Single nucleotide polymorphism MBL Mannose-binding lectin PRM Pattern recognition molecule TAFI Thrombin-activatable fibrinolysis inhibitor IL Interleukin MODS Multiorgan dysfunction SIRS Systemic inflammatory response syndrome LCOS Low cardiac output syndrome CRD Carbohydrate-recognition domain Int. J. Mol. Sci. 2020, 21, 5483 10 of 14

CL-L1 Collectin liver-1 (collectin-10) CL-K1 Collectin kidney-1 (collectin-11) SP-A Surfactant protein A SP-D Surfactant protein D LPS HIV Human immunodeficiency virus D-Man D-MANNOSE D-GlcNAc N-ACETYL-D-GLUCOSAMINE D-Gal D-GALACTOSE L-Fuc L-FUCOSE D-Fuc D-FUCOSE D-ManNAc N-ACETYL-D-MANNOSAMINE CRC Colorectal cancer MSCs Mesenchymal stem cells

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